Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disease that occurs when motor neurons degenerate, causing the muscles under their control to atrophy (Amyotrophic Lateral Sclerosis Information Page, National Institute of Neurological Disorders and Stroke). Symptoms may include loss of motor control in one's extremities, twitching, cramping and difficulties in speaking, swallowing and breathing. Death usually occurs within 5 years of diagnosis. Neuroprotective treatment of patients suffering from ALS is in its early stages (Ludolph, A. C. et al.). The etiology and pathogenesis of ALS are not known, although a number of hypotheses have been advanced (Physician's Desk Reference, 2002) One hypothesis is that motor neurons, made vulnerable through either genetic predisposition or environmental factors, are injured by glutamate (Id.). There is evidence that mitochondrial damage and oxidative stress plays a role in human sporadic ALS (Ludolph A. C. et al.; Vielhaber S. et al.). In some cases of familial ALS, the enzyme superoxide dismutase has been found to be defective (Physician's Desk Reference, 2002).
Currently, transgenic mice carrying multiple copies of the human G93A mutation are considered to be the best model system for anterior horn cell degenerations such as ALS (Ludolph A. C. et al.; Gurney M. E. et al., Science (1994); Gurney M. E. et al., Ann. Neurol. (1996)). In this model the cell degeneration is caused by a biological factor responsible for the etiology of the disease in some patients. The model is well-characterized on the morphological and functional level and is comparatively robust.
Neuropathological studies of the G93A mice support current ideas stressing that mitochondrial damage and oxidative stress are important pathogenetic factors for anterior horn cell disease since mitochondrial swelling and vacuolization are among the earliest pathologic features observed (Ferrante R. J. et al.; Wong P. C. et al.; Kong J. et al.). There is evidence that this mechanism also plays a role in human sporadic ALS (Ludolph A. C. et al.; Vielhaber S. et al.).
Riluzole, a membrane-stabilizing drug, has been shown to have a therapeutic effect on ALS. Riluzole is a member of the benzothiazole class (Physician's Desk Reference, (2002)). Chemically, riluzole is 2-amino-6-trifluoromethoxy benzothiazole and has a molecular formula of C8H5F3N2OS (Id.). Its structural formula is as follows:

It has a molecular weight of 234.2. Pharmacological properties of riluzole include an inhibitory effect on glutamate release (Id.) mediated by inactivation of voltage-dependent sodium channels and by its ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors.
RILUTEK®, which has been FDA-approved for the treatment of ALS, is a capsule-shaped, white, film-coated tablet for oral administration containing 50 mg of riluzole. The recommended dose for RILUTEK® is 50 mg every 12 hours. (Physician's Desk Reference, (2002), p. 772-775, the entire contents of which are hereby incorporated by reference.)
Rasagiline has been shown to have certain neuroprotective effects. Rasagiline has the chemical name R(+)-N-propargyl-1-aminoindan and its structural formula is:

Rasagiline is believed to reduce oxidative stress by inhibition of monoamine oxidase B (MAO-B) (Youdim M. B. H. et al.). However, neuroprotection with rasagiline has also been linked to apoptosis, presumably by a bcl-2-like effect on the mitochondrial membrane potential (Maruyama W. et al.). Neuroprotection with rasagiline has been demonstrated in stroke models (Speiser Z. et al.; Eliash S. et al.) and in models of traumatic head injury (Huang W. et al.). However, rasagiline has not been suggested to be effective for the treatment of ALS.
Rasagiline, its salts, preparation and use for the treatment of Parkinson's disease, memory disorders and other neurological disorders have been the subject of numerous patents, including U.S. Pat. Nos. 5,387,612, 5,453,446, 5,457,133, 5,668,181, 5,576,353, 5,532,415, 5,599,991, 5,786,390, 5,519,061, 5,891,923, 5,744,500 and 6,316,504, the contents of which are incorporated by reference.
The in vivo interactions between two drugs, such as those of the subject invention, are complex. The effects of a drug are related to its absorption, distribution, and elimination. When two drugs are introduced into the body, each drug can affect the absorption, distribution, and elimination of the other and hence, alter the effects of the other. For instance, one drug may inhibit, activate or induce the production of enzymes involved in a metabolic route of elimination of the other drug (“Guidance for Industry”). Thus, when two drugs are administered to treat the same disease, it is unclear whether each will complement the therapeutic activity of the other, have no effect, or interfere with the therapeutic activity of the other.
Not only may the interaction between two drugs affect the intended therapeutic activity of each drug, but the interaction may increase the levels of toxic metabolites (“Guidance for Industry”). The interaction may also heighten or lessen the side effects of each drug.
Additionally, it is difficult to predict when the effects of the interaction between the two drugs will become manifest. For example, metabolic interactions between drugs may become apparent upon the initial administration of the second drug, after the two have reached a steady-state of concentration or even upon discontinuation of one of the drugs (“Guidance for Industry”).
Thus, the success of one drug or each drug separately in an in vitro model, an animal model or even in humans may not translate into success of the administration of both drugs in humans.
The present invention presents the unexpected discovery that rasagiline is effective for the treatment of ALS. Also disclosed is that the combination of rasagiline with riluzole is more effective for treating ALS than either drug alone. In particular, the results of rasagiline used in G93A mice alone or in combination with riluzole indicated that oral administration of rasagiline produced a dose-dependent improvement in motor performance and convincingly extended survival in these mice.